Using the anticonvulsant carbamazepine, we have documented acute response in approximately two-thirds of acutely manic patients and one-third of acutely depressed patients. Lithium augmentation of inadequate response is also observed, in both mania and depression in spite of greater decrements in T3 and T4 than with either agent alone. Long-term prophylaxis of both manic and depressive episodes has also been documented with carbamazepine, although a subgroup of patients show loss of efficacy over time. This may represent the development of patients of tolerance and appears to occur in patients with the most rapidly deteriorating prior course of illness. Patients who are inadequately responsive to carbamazepine may respond to valproate and vice-versa. Many of the correlates of poor response to lithium (severe, dysphoric mania, rapid cycling, non-familial illness) may be associated with good response to carbamazepine or valproate. Thus, carbamazepine and valproate appear to be important clinical options in lithium-refractory bipolar illness. Good responses have not been observed to the anticonvulsant phenytoin, while clonazepam may be a useful acute adjunct for breakthrough manic episodes and their associated insomnia. A clinical trial of the anticonvulsant calcium channel blocker nimodipine has been instituted with promising results in only one of the first several patients treated. We are attempting to elucidate clinical and biological markers of differential response to lithium and the anticonvulsant agents carbamazepine and valproate.